Diabetic polyneuropathies: update on research definition, diagnostic criteria and estimation of severity.

Prior to a joint meeting of the Neurodiab Association and International Symposium on Diabetic Neuropathy held in Toronto, Ontario, Canada, 13-18 October 2009, Solomon Tesfaye, Sheffield, UK, convened a panel of neuromuscular experts to provide an update on polyneuropathies associated with diabetes (Toronto Consensus Panels on DPNs, 2009). Herein, we provide definitions of typical and atypical diabetic polyneuropathies (DPNs), diagnostic criteria, and approaches to diagnose sensorimotor polyneuropathy as well as to estimate severity. Diabetic sensorimotor polyneuropathy (DSPN), or typical DPN, usually develops on long-standing hyperglycaemia, consequent metabolic derangements and microvessel alterations. It is frequently associated with microvessel retinal and kidney disease-but other causes must be excluded. By contrast, atypical DPNs are intercurrent painful and autonomic small-fibre polyneuropathies. Recognizing that there is a need to detect and estimate severity of DSPN validly and reproducibly, we define subclinical DSPN using nerve conduction criteria and define possible, probable, and confirmed clinical levels of DSPN. For conduct of epidemiologic surveys and randomized controlled trials, it is necessary to pre-specify which attributes of nerve conduction are to be used, the criterion for diagnosis, reference values, correction for applicable variables, and the specific criterion for DSPN. Herein, we provide the performance characteristics of several criteria for the diagnosis of sensorimotor polyneuropathy in healthy subject- and diabetic subject cohorts. Also outlined here are staged and continuous approaches to estimate severity of DSPN.

Signs and symptoms versus nerve conduction studies to diagnose diabetic sensorimotor polyneuropathy: Cl vs. NPhys trial.

The purpose was to test whether physicians can validly and reproducibly diagnose diabetic sensorimotor polyneuropathy (DSPN). Twelve physicians assessed 24 patients with diabetes mellitus (DM) on consecutive days (576 examinations) with physical features and voice disguised. Results were compared to gold standard 75% group diagnosis (dx) and a nerve conduction score (Sigma5 NC nds). Masking of patients was achieved. Reproducibility measured by the kappa coefficient and compared to Sigma5 NC nd varied considerably among physicians: median and ranges: signs 0.8 (0.32-1.0); symptoms 0.79 (0.36-1.0), and diagnoses 0.47 (0.33-0.84), both low and high scores indicating poor performance. There was substantial agreement between 75% group dx and confirmed NC abnormality (abn). As compared to Sigma5 NC, individual physicians' clinical dx was excessively variable and frequently inaccurate. Study physician dx from signs and symptoms were excessively variable, often overestimating DSPN. Specific approaches to improving clinical proficiency should be tested.

Thrombin generation as a predictor of radiotherapy induced skin erythema.

BACKGROUND AND PURPOSE: Biological mechanisms underlying radiation induced erythema remain largely unknown, with no simple way to accurately predict or prevent extreme cases. Based on the recent findings in patients suffering from chronic urticaria, we sought to determine if similar mechanisms of hypercoagulation contributed to comparable skin reactions during radiotherapy. MATERIALS AND METHODS: Plasma levels of prothrombin factor 1+2 (F1+2), D-dimers and plasminogen activator inhibitor-1 (Pai-1) were tested in 32 women undergoing irradiation following breast conserving surgery for early breast cancer. Reflectance spectrophotometry was used to objectively assess erythema throughout the treatment by measuring the amount of light reflected from the skin surface as a function of wavelength. Correlations between peak levels of erythema and plasma biomarkers were then assessed. RESULTS: Individual peak reflectance readings generally occurred between day 29 of treatment and 2 weeks post radiotherapy, and represented a median increase of 66% (range: 11-146%; p<0.001) from baseline. Peak reflectance correlated with F1+2 and Pai-1 levels measured both at baseline and day 29 of treatment, and multivariate analysis indicated that these two baseline measurements were the best predictors of peak reflectance, accounting for 59% of the variability in erythema (p=0.000004). CONCLUSIONS: Patients with signs of intravascular thrombin generation are at higher risk of radiotherapy-induced skin reactions, providing a new therapeutic avenue for possibly predicting and preventing this side effect of cancer treatment.

Intensive intraoperative insulin therapy versus conventional glucose management during cardiac surgery: a randomized trial.

BACKGROUND: It is not known whether rigorous intraoperative glycemic control reduces death and morbidity in cardiac surgery patients. OBJECTIVE: To compare outcomes of intensive insulin therapy during cardiac surgery with those of conventional intraoperative glucose management. DESIGN: A randomized, open-label, controlled trial with blinded end point assessment. SETTING: Tertiary care center. PATIENTS: Adults with and without diabetes who were undergoing on-pump cardiac surgery. MEASUREMENTS: The primary outcome was a composite of death, sternal infections, prolonged ventilation, cardiac arrhythmias, stroke, and renal failure within 30 days after surgery. Secondary outcome measures were length of stay in the intensive care unit and hospital. INTERVENTION: Patients were randomly assigned to receive continuous insulin infusion to maintain intraoperative glucose levels between 4.4 (80 mg/dL) and 5.6 mmol/L (100 mg/dL) (n = 199) or conventional treatment (n = 201). Patients in the conventional treatment group were not given insulin during surgery unless glucose levels were greater than 11.1 mmol/L (>200 mg/dL). Both groups were treated with insulin infusion to maintain normoglycemia after surgery. RESULTS: Mean glucose concentrations were statistically significantly lower in the intensive treatment group at the end of surgery (6.3 mmol/L [SD, 1.6] [114 mg/dL {SD, 29}] in the intensive treatment group vs. 8.7 mmol/L [SD, 2.3] [157 mg/dL {SD, 42}] in the conventional treatment group; difference, -2.4 mmol/L [95% CI, -2.8 to -1.9 mmol/L] [-43 mg/dL {CI, -50 to -35 mg/dL}]). Eighty two of 185 patients (44%) in the intensive treatment group and 86 of 186 patients (46%) in the conventional treatment group had an event (risk ratio, 1.0 [CI, 0.8 to 1.2]). More deaths (4 deaths vs. 0 deaths; P = 0.061) and strokes (8 strokes vs. 1 strokes; P = 0.020) occurred in the intensive treatment group. Length of stay in the intensive care unit (mean, 2 days [SD, 2] vs. 2 days [SD, 3]; difference, 0 days [CI, -1 to 1 days]) and in the hospital (mean, 8 days [SD, 4] vs. 8 days [SD, 5]; difference, 0 days [CI, -1 to 0 days]) was similar for both groups. LIMITATIONS: This single-center study used a composite end point and could not examine whether outcomes differed by diabetes status. CONCLUSIONS: Intensive insulin therapy during cardiac surgery does not reduce perioperative death or morbidity. The increased incidence of death and stroke in the intensive treatment group raises concern about routine implementation of this intervention.

Outcomes and relapse patterns following chemotherapy in advanced Hodgkin lymphoma in the positron emission tomography era.

BACKGROUND: This study evaluated relapse patterns and survival in advanced Hodgkin lymphoma (HL) patients treated with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) with positron emission tomography (PET) used for staging and response assessment. PATIENTS AND METHODS: Patients aged 18 years or above with newly diagnosed histologically proven Stage III or IV HL treated with ABVD at Calvary Mater Newcastle from January 2005 to December 2012 were included in this study. All patients underwent pre-chemotherapy staging with 18F-fluorodeoxyglucose PET or PET/computed tomography and post-chemotherapy PET or PET/computed tomography for the assessment of response. RESULTS: Forty-three patients were included in the study. The 5-year disease-free survival, progression-free survival and overall survival were 88%, 74% and 86%, respectively. PET complete response was seen in 35 patients (81%), and the 5-year overall survival for this group was 94%. Relapse following a PET complete response was low (three patients) and occurred predominantly at the initial sites of disease. Four of five patients with bulky disease received consolidative radiotherapy and no in-field relapses were observed. CONCLUSION: Advanced stage HL with a PET complete response following ABVD is associated with an excellent prognosis.

Energy expenditure, sex, and endogenous fuel availability in humans.

Adipose tissue lipolysis supplies circulating FFAs, which largely meet lipid fuel needs; however, excess FFAs, can contribute to the adverse health consequences of obesity. Because "normal" FFA release has not been well defined, average (mean of 4 days) basal FFA release and its potential regulation factors were measured in 50 lean and obese adults (25 women). Resting energy expenditure (REE), but not body composition, predicted most of the interindividual variation in FFA release. There was a significant, positive linear relationship between palmitate release and REE; however, women released approximately 40% more FFA than men relative to REE. Neither plasma palmitate concentrations nor respiratory quotient by indirect calorimetry differed between men and women. Glucose release rates were not different in men and women whether related to REE or fat free mass. These findings indicate that nonoxidative FFA clearance is greater in women than in men. This could be an advantage at times of increased fuel needs. We conclude that "normal" adipose tissue lipolysis is different in men and women and that the fuel export role of adipose tissue in obesity will need to be reassessed.

Modeling chronic glycemic exposure variables as correlates and predictors of microvascular complications of diabetes.

OBJECTIVE: The degree to which chronic glycemic exposure (CGE) (fasting plasma glucose [FPG], HbA1c [A1C], duration of diabetes, age at onset of diabetes, or combinations of these) is associated with or predicts the severity of microvessel complications is unsettled. Specifically, we test whether combinations of components correlate and predict complications better than individual components. RESEARCH DESIGN AND METHODS: Correlations and predictions of CGE and complications were assessed in the Rochester Diabetic Neuropathy Study, a population-based, cross-sectional, and longitudinal epidemiologic survey of 504 patients with diabetes followed for up to 20 years. RESULTS: In multivariate analysis, A1C and duration of diabetes (and to a lesser degree age at onset of diabetes but not FPG) were the main significant CGE risk covariates for complications. A derived glycemic exposure index (GE(i)) correlated with and predicted complications better than did individual components. Composite or staged measures of polyneuropathy provided higher correlations and better predictions than did dichotomous measures of whether polyneuropathy was present or not. Generally, the mean GE(i) was significantly higher with increasing stages of severity of complications. CONCLUSIONS: A combination of A1C, duration of diabetes, and age at onset of diabetes (a mathematical index, GE(i)) correlates significantly with complications and predicts later complications better than single components of CGE. Serial measures of A1C improved the correlations and predictions. For polyneuropathy, continuous or staged measurements performed better than dichotomous judgments. Even with intensive assessment of CGE and complications over long times, only about one-third of the variability of the severity of complications is explained, emphasizing the role of other putative risk covariates.

Pyridostigmine treatment trial in neurogenic orthostatic hypotension.

BACKGROUND: Midodrine hydrochloride is the only drug demonstrated in a placebo-controlled treatment trial to improve orthostatic hypotension (OH) but it significantly worsens supine hypertension. By enhancing ganglionic transmission, pyridostigmine bromide can potentially ameliorate OH without worsening supine hypertension. OBJECTIVE: To evaluate the efficacy of a single 60-mg dose of pyridostigmine bromide, alone or in combination with a subthreshold (2.5 mg) or suprathreshold (5 mg) dose of midodrine hydrochloride, compared with placebo. DESIGN: We report a double-blind, randomized, 4-way cross-over study of pyridostigmine in the treatment of neurogenic OH. A total of 58 patients with neurogenic OH were enrolled. After 1 day of baseline measurements, patients were given 4 treatments (3 active treatments [60 mg of pyridostigmine bromide; 60 mg of pyridostigmine bromide and 2.5 mg of midodrine hydrochloride; 60 mg of pyridostigmine bromide and 5 mg of midodrine hydrochloride] and a placebo) in random order on successive days. Blood pressure (BP) and heart rate were measured, both supine and standing, immediately before treatment and hourly for 6 hours after the treatment was given. RESULTS: No significant differences were seen in the supine BP, either systolic (P = .36) or diastolic (P = .85). In contrast, the primary end point of the fall in standing diastolic BP was significantly reduced (P = .02) with treatment. Pairwise comparison showed significant reduction by pyridostigmine alone (BP fall of 27.6 mm Hg vs 34.0 mm Hg with placebo; P = .04) and pyridostigmine and 5 mg of midodrine hydrochloride (BP fall of 27.2 mm Hg vs 34.0 mm Hg with placebo; P = .002). Standing BP improvement significantly regressed with improvement in OH symptoms. CONCLUSIONS: Pyridostigmine significantly improves standing BP in patients with OH without worsening supine hypertension. The greatest effect is on diastolic BP, suggesting that the improvement is due to increased total peripheral resistance.

Combined-modality therapy for primary central nervous system lymphoma: long-term data from a Phase II multicenter study (Trans-Tasman Radiation Oncology Group).

PURPOSE: To assess, in a multicenter setting, the long-term outcomes of a brief course of high-dose methotrexate followed by radiotherapy for patients with primary central nervous system lymphoma (PCNSL). METHODS AND MATERIALS: Forty-six patients were entered in a Phase II protocol consisting of methotrexate (1 g/m(2) on Days 1 and 8), followed by whole-brain irradiation (45-50.4 Gy). The median follow-up time was 7 years, with a minimum follow-up of 5 years. RESULTS: The 5-year survival estimate was 37% (+/-14%, 95% confidence interval [CI]), with progression-free survival being 36% (+/-15%, 95% CI), and median survival 36 months. Of the original 46 patients, 10 were alive, all without evidence of disease recurrence. A total of 11 patients have developed neurotoxicity, with the actuarial risk being 30% (+/-18%, 95% CI) at 5 years but continuing to increase. For patients aged>60 years the risk of neurotoxicity at 7 years was 58% (+/-30%, 95% CI). CONCLUSION: Combined-modality therapy, based on high-dose methotrexate, results in improved survival outcomes in PCNSL. The risk of neurotoxicity for patients aged>60 years is unacceptable with this regimen, although survival outcomes for patients aged>60 years were higher than in many other series.

Adverse event reporting and developments in radiation biology after normal tissue injury: International Atomic Energy Agency consultation.

PURPOSE: Recent research has enhanced our understanding of radiation injury at the molecular-cellular and tissue levels; significant strides have occurred in standardization of adverse event reporting in clinical trials. In response, the International Atomic Energy Agency, through its Division of Human Health and its section for Applied Radiation Biology and Radiotherapy, organized a consultation meeting in Atlanta (October 2, 2004) to discuss developments in radiobiology, normal tissue reactions, and adverse event reporting. METHODS AND MATERIALS: Representatives from cooperative groups of African Radiation Oncology Group, Curriculo Radioterapeutica Ibero Latino Americana, European Organization for Research and Treatment of Cancer, National Cancer Institute of Canada Clinical Trials Group, Radiation Therapy Oncology Group, and Trans-Tasman Radiation Oncology Group held the meeting discussion. RESULTS: Representatives of major radiotherapy groups/organizations and prominent leaders in radiotherapy discussed current understanding of normal tissue radiobiologic effects, the design and implementation of future clinical and translational projects for normal tissue injury, and the standardization of adverse-event reporting worldwide. CONCLUSIONS: The consensus was to adopt NCI comprehensive adverse event reporting terminology and grading system (CTCAE v3.0) as the new standard for all cooperative group trials. Future plans included the implementation of coordinated research projects focusing on normal tissue biomarkers and data collection methods.

Monotonicity of nerve tests in diabetes: subclinical nerve dysfunction precedes diagnosis of polyneuropathy.

OBJECTIVE: The objective of this study was to test whether monotone worsening of nerve function, attributable to diabetes, can be demonstrated before criteria for diabetic sensorimotor polyneuropathy (DSPN) have been met. Which nerve tests are best? RESEARCH DESIGN AND METHODS: From a prevalence cohort of 504 individuals in the Rochester Diabetic Neuropathy study (RDNS), we identified 238 individuals (group 1) who at first examination were without polyneuropathy (DSPN) by a sum score of the normal deviates (from percentiles) of five attributes of nerve conduction of the legs (i.e., their five nerve conduction normal deviate values were <97.5th percentile) and were followed longitudinally two or more times. Of these 238, 90 (group 2) were followed six or more times at yearly or bi-yearly intervals. We compared different nerve tests for the ones most sensitive and reliable in showing latent nerve dysfunction and monotone (the extent to which a variable measured repeatedly over time reveals a significant trend of worsening or improvement). RESULTS: In group 1 patients, the mean sum score of five attributes of nerve conduction (sigma 5 NC nds) at baseline was 1.08 and at the last examination (only patients with Sigma 5 NC nds <97.5th percentile) was 3.63, markedly higher than that in healthy subjects (only of individuals with Sigma 5 NC nds <97.5th percentile) (-0.12), indicating a subtle latent shift of nerve conduction tests toward abnormality. Serial evaluations of many individual and especially sum scores of nerve conduction tests in group 2 patients showed statistically significant worsening with time, even when nerve conduction tests were still well within normal limits. Neurologic signs also worsened but barely to significant levels; however, symptoms and quantitative sensation tests did not. Considering the composite score sigma 5 NC nds, 42 (of 90 group 2 patients) showed significant worsening, 22 were still without DSPN by nerve conduction test criteria, and some were even below the 50th percentile at the last evaluation. CONCLUSIONS: Subtle and latent functional worsening of nerve conduction can be demonstrated even before nerve conduction test criteria for DSPN have been met. For demonstrating monotone worsening, the order (from best to worst) of tests was: some composite scores of nerve conduction and individual attributes of nerve conduction. We did not show monotone worsening of symptoms or of quantitative sensation test results. In multivariate analysis of risk factors and their association with worsening sigma 5 NC nds, 24-h microalbuminuria (a marker of microvessel disease) was found to be a significant covariate, an indication that the asymptomatic alterations of nerve conduction are meaningful.

Increasing serum betahydroxybutyrate concentrations during the 72-hour fast: evidence against hyperinsulinemic hypoglycemia.

OBJECTIVE: We have determined whether the behavior of betahydroxybutyrate (BOHB) during the 72-h fast of persons without evidence of hyperinsulinemic or any form of organic hypoglycemia might provide indicators of a negative fast. DESIGN: Twenty-one patients with surgically confirmed insulinoma and 34 patients with negative 72-h fasts had BOHB measured every 6 h until Whipple's triad in the former and until 72-h in the latter. RESULTS: Quadratic regression curves of BOHB from the negative fasts showed the typical curve to be flat initially, then increase in a manner that was roughly linear. Using time-specific medians, the changes were: 12-18 h, 0% increase; 18-36 h, 333% increase; 36-54 h, 210% increase, and 54-72 h, 167% increase. In contrast, patients with insulinoma had suppressed BOHB concentrations. Two successive BOHB values in excess of the 18-h level seemed to portend a negative fast. By using the previously published criterion of BOHB more than 2.7 mmol/liter (a surrogate for hypoinsulinemia and thereby an indicator of a negative fast), 74% of persons with a negative fast reached this level before the 72-h point. CONCLUSIONS: Serial measurements of BOHB during the 72-h fast have the potential to provide not only clues during the fast that it will ultimately be negative, but also the opportunity to truncate the fast if the endpoint BOHB criterion for a negative fast is met before 72 h.

Costing the components of pain management: analysis of Trans-Tasman Radiation Oncology Group trial (TROG 96.05): one versus five fractions for neuropathic bone pain.

BACKGROUND AND PURPOSE: Bone metastases causing neuropathic pain (NBP) have traditionally been treated with fractionated radiotherapy (RT). A recently reported randomised Trans-Tasman Radiation Oncology Group trial (TROG 96.05) supports this approach in many cases [Roos DE, Turner SL, O'Brien PC et al. Randomised trial of 8 Gy in 1 versus 20 Gy in 5 fractions of radiotherapy for neuropathic pain due to bone metastases (Trans-Tasman Radiation Oncology Group, TROG 96.05). Radiother Oncol 2005;75:54-63]. This study sought to compare costs to the Australian health-care system for patients receiving 1 versus 5 fractions for NBP. PATIENTS AND METHODS: The RT and medication costs for 245 patients treated on TROG 96.05 were determined from trial data out to 3 months from RT. Admission costs and causes were derived from hospital records. RESULTS: RT costs (including re-treatments) were calculated to be 222 and 724 Australian dollars (A dollars) per patient for the 8 Gy/1 and 20 Gy/5 arms, respectively. This difference increased when analgesics (A dollars 192 versus A dollars 229) and related hospital admissions (A dollars 1,411 versus A dollars 1,893) were considered. Sensitivity analysis demonstrated an incremental cost saving of between A dollars 795 and A dollars 1,468 for single fraction RT. Admission rates had the strongest potential to distort cost differences. CONCLUSIONS: Clinical outcomes are paramount in choice of fractionation scheme but are optimally considered in the light of economic implications. Overall cost differences between fractionation schedules may vary greatly from those incurred by the RT treatment centre alone. Ideally, such economic evaluations should be planned at the outset of a trial.

Randomized trial of 8 Gy in 1 versus 20 Gy in 5 fractions of radiotherapy for neuropathic pain due to bone metastases (Trans-Tasman Radiation Oncology Group, TROG 96.05).

BACKGROUND AND PURPOSE: Despite numerous randomized trials investigating radiotherapy (RT) fractionation schedules for painful bone metastases, there are very few data on RT for bone metastases causing pain with a neuropathic component. The Trans-Tasman Radiation Oncology Group undertook a randomized trial comparing the efficacy of a single 8 Gy (8/1) with 20 Gy in 5 fractions (20/5) for this type of pain. MATERIALS AND METHODS: Eligible patients had radiological evidence of bone metastases from a known malignancy with no change in systemic therapy within 6 weeks before or anticipated within 4 weeks after RT, no other metastases along the distribution of the neuropathic pain and no clinical or radiological evidence of cord/cauda equina compression. All patients gave written informed consent. Primary endpoints were pain response within 2 months of commencement of RT and time to treatment failure (TTF). The hypothesis was that 8/1 is at least as effective as 20/5 and the planned sample size was 270 patients. RESULTS: Between February 1996 and December 2002, 272 patients were randomized (8/1:20/5=137:135) from 15 centres (Australia 11, New Zealand 3, UK 1). The commonest primary cancers were lung (31%), prostate (29%) and breast (8%); index sites were spine (89%), rib (9%), other (2%); 72% of patients were males and the median age was 67 (range 29-89). The median overall survival (95% CI) for all randomized patients was 4.8 mo (4.2-5.7 mo). The intention-to-treat overall response rates (95% CI) for 8/1 vs 20/5 were 53% (45-62%) vs 61% (53-70%), P=0.18. Corresponding figures for complete response were 26% (18-34%) vs 27% (19-35%), P=0.89. The estimated median TTFs (95% CI) were 2.4 mo (2.0-3.3 mo) vs 3.7 mo (3.1-5.9 mo) respectively. The hazard ratio (95% CI) for the comparison of TTF curves was 1.35 (0.99-1.85), log-rank P=0.056. There were no statistically significant differences in the rates of re-treatment, cord compression or pathological fracture by arm. CONCLUSIONS: 8/1 was not shown to be as effective as 20/5, nor was it statistically significantly worse. Outcomes were generally poorer for 8/1, although the quantitative differences were relatively small.

Trends in the mortality burden associated with diabetes mellitus: a population-based study in Rochester, Minn, 1970-1994.

BACKGROUND: The prevalence of diabetes mellitus (DM) has increased markedly in recent decades, but trends in the mortality burden associated with DM are unclear. Therefore, we analyzed population-based longitudinal data to address this issue. METHODS: The community-based medical records of all Rochester residents 45 years and older who died between January 1, 1970, and December 31, 1994, were reviewed to identify those who met the standardized criteria for DM before death. Trends over successive quinquenniums were assessed for the proportion of all deaths in the community of persons with prevalent DM, for mortality rates for persons with and without DM, and for the distribution of causes of death among decedents with and without DM. RESULTS: Of 10 152 total deaths in 1970-1994, 1384 (13.6%) met the criteria for prevalent DM. Between 1970-1974 and 1990-1994, the proportion of decedents with DM increased by 48.2%. Mortality rates for persons with and without DM declined by 13.8% and 21.4%, respectively. This disparity in mortality trends was most apparent for older women and younger men. There were temporal declines in the proportion of all persons dying of cardiovascular disease, but temporal declines in persons dying of cerebrovascular disease were found only in decedents without DM. CONCLUSIONS: The mortality burden associated with DM increased significantly between 1970 and 1994, probably due to increases in DM incidence and smaller declines in mortality for persons with DM relative to those without DM. In the absence of improved DM prevention and treatment, the steady declines in mortality observed for the general population since the 1960s will likely begin to slow or even reverse.

Autonomic symptoms and diabetic neuropathy: a population-based study.

OBJECTIVE: The prevalence of autonomic symptoms and deficits in certain systems is known, but a comprehensive autonomic symptom profile in diabetes is not available. We aimed to estimate this using a laboratory evaluation of autonomic function and a validated self-report measure of autonomic symptoms in patients and matched control subjects from the population-based Rochester Diabetic Neuropathy Study. RESEARCH DESIGN AND METHODS: Participants included 231 patients with diabetes (type 1, n=83; type 2, n=148) and 245 healthy age-matched control subjects. We assessed symptoms using a validated self-report instrument (Autonomic Symptom Profile) and evaluated the severity and distribution of autonomic deficits (cardiovagal, sudomotor, adrenergic) with the objective, laboratory-based Composite Autonomic Severity Score (CASS). RESULTS: Autonomic symptoms were present more commonly in type 1 than in type 2 diabetes, with symptoms of orthostatic intolerance, secretomotor, urinary control, diarrhea, and sleep disturbance and pupillomotor, vasomotor, and erectile dysfunction significantly increased over healthy control subjects in type 2 diabetic patients. The prevalence of autonomic impairment was 54% in type 1 and 73% in type 2 diabetic patients. Severity of autonomic failure was mild overall (mean CASS 2.3; maximum 10), with orthostatic hypotension occurring in 8.4 and 7.4% of type 1 and 2 diabetic patients, respectively. Fourteen percent of patients had a CASS > or =5, indicating moderate to severe generalized autonomic failure. The correlation of symptoms with autonomic deficits (CASS) was better in type 1 than type 2 diabetic subjects and was weak overall. CONCLUSIONS: These findings indicate that autonomic symptoms and deficits are common in diabetes, but mild in severity, and that the correlation between symptom scores and deficits is overall weak in mild diabetic neuropathy, emphasizing the need to separately evaluate autonomic symptoms.

The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial.

OBJECTIVE: Because alpha-lipoic acid (ALA), a potent antioxidant, prevents or improves nerve conduction attributes, endoneurial blood flow, and nerve (Na(+) K(+) ATPase activity in experimental diabetes and in humans and may improve positive neuropathic sensory symptoms, in this report we further assess the safety and efficacy of ALA on the Total Symptom Score (TSS), a measure of positive neuropathic sensory symptoms. RESEARCH DESIGN AND METHODS: Metabolically stable diabetic patients with symptomatic (stage 2) diabetic sensorimotor polyneuropathy (DSPN) were randomized to a parallel, double-blind study of ALA (600 mg) (n = 60) or placebo (n = 60) infused daily intravenously for 5 days/week for 14 treatments. The primary end point was change of the sum score of daily assessments of severity and duration of TSS. Secondary end points were sum scores of neuropathy signs (NIS), symptoms (NSC), attributes of nerve conduction, quantitative sensation tests (QSTs), and an autonomic test. RESULTS: At randomization, the groups were not significantly different by the criteria of metabolic control or neuropathic end points. After 14 treatments, the TSS of the ALA group had improved from baseline by an average of 5.7 points and the placebo group by an average of 1.8 points (P < 0.001). Statistically significant improvement from baseline of the ALA, as compared with the placebo group, was also found for each item of the TSS (lancinating and burning pain, asleep numbness and prickling), NIS, one attribute of nerve conduction, and global assessment of efficacy. CONCLUSIONS: Intravenous racemic ALA, a potent antioxidant, rapidly and to a significant and meaningful degree, improved such positive neuropathic sensory symptoms as pain and several other neuropathic end points. This improvement of symptoms was attributed to improved nerve pathophysiology, not to increased nerve fiber degeneration. Because of its safety profile and its effect on positive neuropathic sensory symptoms and other neuropathic end points, this drug appears to be a useful ancillary treatment for the symptoms of diabetic polyneuropathy.

Familial clustering of stroke according to proband age at onset of presenting ischemic stroke.

BACKGROUND AND PURPOSE: The magnitude of inherited risk of stroke may lessen with age, and this would have implications for optimizing genomic approaches to identifying genetic risk factors for stroke. We investigated the relationship between age and inherited risk of stroke. METHODS: Family histories of stroke were obtained in systematic interviews with 310 adult men and women with recent CT- or MR-confirmed ischemic stroke. Probability of stroke in first-degree relatives was analyzed by logistic regression, adjusting for sibship size. RESULTS: The probability of having a sibling with stroke increased as proband age at stroke presentation increased. Per decade increase in proband age, the odds ratio was 1.65 (95% confidence interval [CI], 1.20 to 2.28; P=0.002) for a concordant sibling and 1.69 (95% CI, 1.15 to 2.49; P=0.008) for >or=2 first-degree relatives with a history of stroke. CONCLUSIONS: Clustering of stroke was not greater in families with probands manifesting symptoms of stroke in earlier than later adulthood. The relationship between proband age and positive family history of stroke does not suggest an upper age-limit cutoff for genomewide linkage studies.

Double-blind, placebo-controlled study of the application of capsaicin cream in chronic distal painful polyneuropathy.

We have completed a 12-week double-blind, placebo-controlled randomized study on the efficacy of the application of capsaicin (CAPS) cream (0.075%) in the treatment of chronic distal painful polyneuropathy. Forty patients were enrolled and 39 completed the study. The 2 limbs were randomly assigned to CAPS or placebo (PLAC). The cream was applied 4 times a day. The first tube contained the active PLAC, methyl nicotinate. In the final 4 weeks (single-blind wash-out phase), PLAC was administered bilaterally. Efficacy was evaluated using the following scales: (1) investigator global, (2) patient global, (3) visual analog (VAS) of pain severity, (4) VAS of pain relief, (5) activities of daily living, and (6) allodynia. Patients were examined at onset and at monthly intervals using a neurologic disability scale, nerve conduction studies, computer-assisted sensory examination for vibration and thermal cooling and warming, QSART (quantitative sudomotor axon reflex test) and quantitative flare response. There was no statistical evidence of efficacy of CAPS cream over PLAC for any of the pain indices. At early time points (1-4 weeks), there were a small number of indices that favored the PLAC. The percent of limbs that improved on the investigator's global scale were 51.3 vs. 53.8 at 4 weeks, 56.4 vs. 64.1 at 8 weeks and 59 vs. 66.7 at 12 weeks for CAPS vs. PLAC; no statistically significant difference was found. All the safety indices showed no difference between sides. We interpret the early hyperalgesia on the CAPS side as being responsible for the better performance of PLAC at early time points. The large percentage of limbs that improved may be a pronounced PLAC response.